ABSTRACT The Georgetown Lombardi Comprehensive Cancer Center (LCCC) Molecular Oncology Program (MO) brings together investigators whose mission is to identify and validate molecular pathways critical to the initiation, progression, maintenance and metastases of cancer. The overall goals of MO are to understand and develop biomarkers for the complex processes of cancer susceptibility, initiation and progression, plus identify novel targets and novel and repurposed anti-cancer agents that show promise because of reduced toxicity against normal cells. To accomplish this mission and goals, MO members perform research under two 2 aims: 1) Define and exploit unique genomic and epigenomic events that initiate and sustain cancer growth and 2) determine the biological mechanisms that underlie stem cell-like phenotypes, altered metabolism and the metastatic spread of cancer cells. A significant advances that reflects progress in Aim 1 by Yi found that Yap modulates the immunosuppressive environment in pancreatic ductal adenocarcinoma (PDAC). For Aim 2, Chung identified theaphenon E treatment significantly decreased ?-OHPdG levels in the liver DNA of Xpa-/- mice that reduced HCC incidence in these mice to 14% from 100% in the controls. The LCCC Consortium is comprised of Georgetown Lombardi Comprehensive Cancer Center, based in Washington, DC (LCCC-DC) and the John Theurer Cancer Center of Hackensack Meridian Health, based in Hackensack, NJ (LCCC-NJ). Accordingly, the LCCC catchment area is defined by the LCCC-DC and LCCC0NJ catchment areas. Led by Jeffrey Toretsky, MD and Benjamin Tycko, MD, PhD, the program has 21 members and 23 associate members from 13 departments across LCCC Consortium institutions. In the current year, MO members are supported by $7.68M ($7.3M LCCC-DC, $385,226 LCCC-NJ) in research grant funding (annual direct costs) of which $2.3M ($1.92M LCCC-DC, $385,226 LCCC-NJ) is peer reviewed and $1.251M (at LCCC-DC) is funded by the National Cancer Institute (NCI). MO is home to four multi-investigator grants. Productivity is demonstrated by 214 cancer-related publications, 23 of which were in journals with an impact factor ? 8. Cancer and program-related publications included 23% inter- programmatic, 22% intra-programmatic, 11% inter- and intra-programmatic and 36% that involved collaborations with another cancer center. MO members collaborate with members of the other three LCCC Research Programs (Breast Cancer Program [BC], Cancer Prevention and Control Program [CPC], and Experimental Therapeutics Program [ET]) and use all nine Shared Resources. To support integrated thematic research, MO houses significant novel technical expertise, including conditionally reprogrammed cells (CRCs), Zevatars, and a BiaCore 4000.